Association between intensity of physical activity and cognitive function in hypertensive patients: a case–control study

Previous studies have shown that a higher intensity of physical activity (PA) is associated with a lower risk of cognitive impairment (CI), whereas hypertension is associated with higher CI. However, there are few studies on the association between PA intensity and cognitive function in hypertensive patients. This study investigated the association between PA intensity and cognitive function in hypertensive patients. A total of 2035 hypertensive patients were included in this study, including 407 hypertensive patients with CI and 1628 hypertensive patients with normal cognitive function matched 1:4 by age and sex. The International Physical Activity Questionnaire-Long Form and the Mini-mental State Examination were used to evaluate PA intensity, total metabolic equivalents, and cognitive function in patients with hypertension. Multivariate logistic regression was used to analyze the correlation between PA intensity and CI in hypertensive patients. The Spearman correlation coefficient was used to analyze the correlation between PA intensity and the total score of each component of the MMSE and the correlation between PA total metabolic equivalents and cardiac structure in hypertensive patients. After adjusting for all confounding factors, PA intensity was negatively associated with CI in hypertensive patients (OR = 0.608, 95% CI: 0.447–0.776, P < 0.001), and this association was also observed in hypertensive patients with education level of primary school and below and junior high school and above (OR = 0.732, 95% CI: 0.539–0.995, P = 0.047; OR = 0.412, 95% CI: 0.272–0.626, P < 0.001). The intensity of PA in hypertensive patients was positively correlated with orientation (r = 0.125, P < 0.001), memory (r = 0.052, P = 0.020), attention and numeracy (r = 0.151, P < 0.001), recall ability (r = 0.110, P < 0.001), and language ability (r = 0.144, P < 0.001). PA total metabolic equivalents in hypertensive patients were negatively correlated with RVEDD and LAD (r = − 0.048, P = 0.030; r = − 0.051, P = 0.020) and uncorrelated with LVEDD (r = 0.026, P = 0.233). Higher PA intensity reduced the incidence of CI in hypertensive patients. Therefore, hypertensive patients were advised to moderate their PA according to their circumstances.


Study design and data sources
All data involved in this case-control study were collected from outpatients or wards of 9 hospitals, including the Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan Hospital of Traditional Chinese Medicine, Jinan Minzu Hospital, Qingzhou People's Hospital, Penglai Hospital of Traditional Chinese Medicine, Tai 'an First People's Hospital, Guangrao County Hospital of Traditional Chinese Medicine, Qufu Hospital of Traditional Chinese Medicine, and Weifang Hospital of Traditional Chinese Medicine.These hypertensive patients were recorded in the hypertension electronic community follow-up system of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine.A total of 4011 hypertensive cases of the system from May 2022 to October 2023 were exported and summarized into Excel tables.After excluding 26 cases with severe missing data among hypertension cases, the total number of included cases was 3985.Hypertension was diagnosed according to one of the following criteria: (1) office systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg on 3 times on different days without using antihypertensive drugs.(2)  If the patient has a history of hypertension and is currently using antihypertensive drugs, hypertension should still be diagnosed even if the blood pressure is < 140/90 mmHg.(3) The average SBP/DBP on 24-h ambulatory blood pressure monitoring ≥ 130/80 mmHg; daytime ≥ 135/85 mmHg; and nighttime ≥ 120/70 mmHg.(4) SBP/ DBP ≥ 135/85 mmHg measured at home 3 times on different days without using antihypertensive drugs 12 .The Mini-mental State Examination (MMSE) assessed cognitive function.Normal cognitive function was defined as an MMSE score between 27 and 30, and CI was defined as an MMSE score < 27 13 .The inclusion criteria were as follows: (1) age between 40 and 79 years old; (2) patients with essential hypertension; (3) signing informed consent; and (4) voluntary completion of the collection of hypertension-related information.Exclusion criteria: (1) patients with various types of secondary hypertension; (2) patients with vascular dementia or cognitive decline due to vascular factors; (3) received new drug clinical trials within the past 3 months; (4) pregnant women, pre-pregnant women, and lactating women; (5) comorbid psychosis and/or psychotropic substance use disorder or dependence; (6) malignant tumors and severely impaired liver, kidney, and heart function.Patients with CI and normal cognitive function were matched by age and sex (1:4), and 2035 patients were enrolled, including 407 patients with CI and 1628 patients with normal cognitive function.

Assessment of cognitive function
The Chinese version of the MMSE can effectively and reliably assess the cognitive function of the Chinese population 14 .The MMSE covers seven simple task domains: time and place, repeated words, arithmetic, language, and motor skills, divided into five sections: orientation (10 points), memory (3 points), attention and calculation (5 points), recall (3 points), and language (9 points), on a scale of 0 to 30, with higher scores indicating better cognitive function 15 .

Assessment of sleep quality
The Pittsburgh Sleep Quality Index (PSQI) is a widely used sleep quality assessment questionnaire with good reliability and validity.The scale consists of 19 items, including 7 elements :(1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) sleep efficiency; (5) sleep disorders; (6) sleeping pills; and (7) daytime dysfunction.Each component is scored on a scale of 0 to 3, and the sum of the seven component scores yields a subjective sleep quality score (range 0 to 21 points).The higher the score, the worse the subjective sleep quality 20 .

Statistical analysis
All statistical analyses were performed using SPSS software (version 26.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism software (version 9.0.0;GraphPad Software, San Diego, CA, USA).Quantitative data were expressed as mean ± standard deviation or median and interquartile range and compared by t-test analysis or Mann-Whitney U test.Qualitative data were expressed as percentages and compared using the Chi-square test.Meanwhile, Pearson's correlation test or Spearman's correlation coefficient test was used to investigate the interrelationships.Multivariate logistic regression analysis was used to adjust for covariates.A two-tailed P-value < 0.05 was considered statistically significant.

Ethics statement
This study followed the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine ((2023) Review No. (109)-KY).Patients in the hypertension electronic community follow-up system signed written informed consent.

Baseline characteristics of hypertensive patients
As shown in Table 1, 407 patients with CI (male/female: 189/218) and 1628 patients with normal cognition (male/female: 756/872) were enrolled.Compared with the control group, the CI group of hypertensive patients had greater age, WC, HC, and PSQI total score (P < 0.05), lower systolic pressure at ordinary times, serum TG, TC, and LDL-C levels, and PA total metabolic equivalent (P < 0.05), and higher proportion of education level of primary school and above, physical work as the type of work, no drinking, no CCB use, and low-intensity PA (P < 0.01).
Vol:.( 1234567890 www.nature.com/scientificreports/ Figure 1 analyses of differences in cognitive function among hypertensive patients with different educational levels using the chi-square test.Compared with hypertensive patients with junior high school education and above, hypertensive patients with primary school education and below had a higher proportion of CI (26.92% vs 13.08%, P < 0.001).

Relationship between PA intensity and cognitive function in hypertensive patients
Table 2 uses multivariate logistic regression to explore the relationship between PA intensity and cognitive function in hypertensive patients.After adjusting for age, type of work, alcohol drinking, CCB, ACEI or ARB, and PSQI total score, PA intensity was negatively associated with CI in hypertensive patients (OR = 0.594, 95% CI: 0.467-0.755,P < 0.001), and the negative relationship still existed in hypertensive patients with education level of primary school and below and junior high school and above (OR = 0.732, 95% CI: 0.541-0.990,P = 0.043; OR = 0.410, 95% CI: 0.275-0.612,P < 0.001).After adjusting for systolic pressure at ordinary times, WC, HC, serum TG, TC, and LDL-C levels, PA intensity was also negatively associated with CI in hypertensive patients (OR = 0.518, 95% CI: 0.415-0.645,P < 0.001), and the relationship was negative in hypertensive patients with education level of primary school and below and junior high school and above (OR = 0.636, 95% CI: 0.479-0.844,P = 0.002; OR = 0.373, 95% CI: 0.255-0.545,P < 0.001).After adjusting for all the above factors, PA intensity was

Correlation between PA intensity and MMSE scores in hypertensive patients
Table 3 uses Spearman's correlation coefficient to analyze the correlation between the intensity of PA and MMSE scores in hypertensive patients.The results showed that PA intensity in hypertensive patients was positively correlated with orientation (r = 0.125, P < 0.001), memory (r = 0.052, P = 0.020), attention and numeracy (r = 0.151, P < 0.001), recall ability (r = 0.110, P < 0.001), and language ability (r = 0.144, P < 0.001).There was no correlation between PA total metabolic equivalent and LVEDD in hypertensive patients (r = 0.026, P = 0.233, Fig. 2A).Compared with hypertensive patients with junior high school education and above, hypertensive patients with primary school education and below had a higher proportion of CI (26.92% vs 13.08%, P < 0.001).Statistically significant value (P < 0.001); CI cognitive impairment.

Discussion
The purpose of this study was to investigate the association between PA intensity and cognitive function in hypertensive patients.The results showed that a higher PA intensity was associated with a lower incidence of CI in hypertensive patients, and this association persisted even after adjusting for all confounding factors.In addition, higher PA intensity still reduced the occurrence of CI in hypertensive patients with education levels of primary school and below and junior high school and above.In hypertensive patients, PA intensity was  www.nature.com/scientificreports/positively correlated with orientation, memory, attention and numeracy, recall ability, and language ability; the total metabolic equivalent of PA was negatively correlated with RVEDD and LAD and uncorrelated with LVEDD.This study analyzed the differences in basic information, auxiliary examination, concomitant medications, and subjective evaluation scale between the CI group of hypertensive patients and the normal cognitive function group of hypertensive patients.The study found that hypertensive CI patients had greater age, WC, HC, and PA total metabolic equivalents, as well as poorer sleep quality, which was similar to the findings of several studies [21][22][23][24] .Among hypertensive patients, patients with CI were more likely to have an education level of primary school and above, do manual work, do not drink alcohol, and do not use CCB compared with those with normal cognitive function.The study found that the proportion of hypertensive patients with early CI who had an education level of primary school and below and were mainly engaged in physical work was higher than that of hypertensive patients with normal cognitive function 25 .A Mendelian randomization study found that older men who were infrequent drinkers and abstained from alcohol had greater odds of CI than those who were regular drinkers 26 .Animal experiments have shown that nifedipine not only increased cerebral blood flow in KK-Ay mice but also reduced high serum insulin levels and the production of superoxide and neural differentiation inhibitor protein Id-1 in KK-Ay mice 27 .This study also found that hypertensive patients with CI have lower systolic pressure at ordinary times and serum TG, TC, and LDL-C levels than hypertensive patients with normal cognitive function, which was inconsistent with the results of mainstream studies but similar to the results of some studies.A longitudinal cohort study showed a U-shaped association between systolic blood pressure and CI in older Chinese adults 28 .A cross-sectional study found that plasma TC, TG, and LDL-C levels were lower in elderly Chinese patients with CI than in those with normal cognitive function, which might be related to the inhibition of neuronal cell growth and functional integrity by low cholesterol 29 .
PA is a modifiable factor.Although the relationship between PA and CI has been less studied clinically in hypertensive patients, there is no shortage of studies on them in other populations.Two cross-sectional studies found that a Korean population that did not achieve moderate to high PA was associated with cognitive decline 11 ; a higher PA level decreased the incidence of MCI in the Chinese population aged ≥ 60 years 30 .Zhong Xia et al. found that PA could be used as a predictor of early CI in hypertensive patients by lasso regression, and the lower the intensity of PA, the higher the risk of early CI in hypertensive patients 25 .Two meta-analyses and systematic reviews found that PA helped reduce the risk of cognitive decline 31,32 .Another systematic review showed that moderate-to-high PA was beneficial for improving cognitive function in different age groups, including learning behavior in children aged 6-13 and 14-18 years, and executive function, global cognition, and attention in people older than 50 years 33 .In addition, systematic review studies from the Chinese elderly population have shown that elevated PA levels reduce the incidence of MCI in the Chinese elderly 34 .This study showed that a higher PA intensity could reduce the occurrence of CI in hypertensive patients, and this relationship also existed in hypertensive patients with primary school and above and junior high school and above, which were similar to the results of the above studies.This study also found that stronger PA intensity was positively correlated with the total score of orientation, memory, attention and numeracy, recall ability, and language ability in hypertensive patients, which was similar to the conclusion of previous studies.Two cross-sectional studies separately found that ≥ 150 min of moderate-to-high-intensity PA reduced the prevalence of limitations in orientation and language ability in older Brazilian adults 35 ; moderate-to-high-intensity PA also improved attention and language scores in older adults in northern China 30 .A Chinese longitudinal study found that higher PA levels helped delay the decline of episodic memory function in Chinese patients with diabetes 36 .In conclusion, a stronger intensity of PA can help reduce the occurrence of CI in hypertensive patients and improve cognitive domains such as orientation, memory, attention and numeracy, recall ability, and language ability in hypertensive patients.
The mechanism by which stronger PA can reduce the occurrence of CI in hypertensive patients may be related to improving cerebral blood supply and perfusion and promoting the growth of central nervous cells.Brain cells maintain normal growth and function by obtaining oxygen, glucose, and other essential nutrients through the cerebral circulation while excluding carbon dioxide, lactate, and other metabolites 37 .Decreased cardiac output and neuronal nitric oxide synthase levels were associated with reduced cerebral blood flow 38,39 , and total cerebral blood flow per 100 ml of brain parenchymal volume was positively correlated with cognitive function 40 .PA increased cardiac output 41 , and exercise increased neuronal nitric oxide synthase levels 42 , both of which improved cerebral blood flow, thereby preventing and delaying cognitive decline.As pro-inflammatory factors, tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) can damage central neuronal cells 43,44 and are associated with the decline of cognitive function 45 ; brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) can protect and promote the development of central neurons 46,47 and improve the cognitive function of patients 48,49 .A meta-analysis found that PA could reduce the levels of TNF-α and CRP, and promote the production of BDNF and IGF-1 in patients with MCI 50 .Hypertension itself could lead to the damage of brain neurons by aggravating oxidative stress in the brain, destroying brain microvessels and the blood-brain barrier, and damaging brain white matter and neurovascular coupling, thereby increasing the risk of CI 51 .Systematic reviews have found that PA can help hypertensive patients better control their blood pressure 52 .Therefore, PA may be more effective in reducing the risk of CI in hypertensive patients.
This study also found that the proportion of CI in hypertensive patients with primary school education and below was higher than that in hypertensive patients with junior high school education and above.Two cross-sectional studies found that Chinese populations with education levels of junior high school and above and primary school reduced the incidence of CI compared with those who were illiterate 53 ; the proportion of illiteracy and primary school education in Chinese elderly with CI was higher compared with those with normal cognitive function 13 .It may be that a higher level of education is associated with greater cognitive reserve, thereby improving the cognitive function of patients 54 .In addition, this study found that PA total metabolic equivalents were negatively correlated with LAD in hypertensive patients, which was different from the results of previous studies.A prospective observational survey found that PA score was positively associated with LAD at 5 and Vol:.( 1234567890 55 ; a case-control study found that PA level was positively associated with LAD in the Chinese population 56 .Differences in the study populations and PA variables may have contributed to the findings of this study being different from those of the other two studies.This study also found that PA total metabolic equivalents were negatively correlated with RVEDD in hypertensive patients, which has rarely been reported in previous studies.There are several limitations to this study.First, this study was a case-control study, and it was not possible to determine the causal relationship between PA intensity and CI in hypertensive patients.Therefore, future prospective cohort studies are warranted to determine this relationship.Second, although the multivariate logistic regression model was used to correct confounders in this study, the possibility of residual bias caused by other relevant confounders not included in this study cannot be ruled out.Finally, the samples included in this study were limited to patients with hypertension who visited outpatient clinics or wards of hospitals in Shandong Province, China, and future studies with large samples and multiple regions are needed.However, this study found that higher PA intensity reduced the occurrence of CI in hypertensive patients, and this relationship also existed in hypertensive patients with education levels of primary school and below and junior school and above.Therefore, it recommends hypertensive patients moderately PA according to their conditions.

Conclusion
This study showed that a higher PA intensity reduced the occurrence of CI in hypertensive patients, and this association was also present in hypertensive patients with education levels of primary school and below and junior high school and above.This mechanism may be related to improving brain blood supply and perfusion and promoting the growth of central nervous cells.Therefore, it recommends hypertensive patients moderately PA according to their conditions.

Figure 2 uses
Figure2uses Spearman's correlation coefficient to analyze the correlation between PA total metabolic equivalent and cardiac structure in hypertensive patients.The total metabolic equivalent of PA was negatively correlated with RVEDD and LAD in hypertensive patients (r = − 0.048, P = 0.030, Fig.2B; r = − 0.051, P = 0.020, Fig.2C).There was no correlation between PA total metabolic equivalent and LVEDD in hypertensive patients (r = 0.026, P = 0.233, Fig.2A).

Figure 1 .
Figure 1.Differences in cognitive function among hypertensive patients with different educational levels.Compared with hypertensive patients with junior high school education and above, hypertensive patients with primary school education and below had a higher proportion of CI (26.92% vs 13.08%, P < 0.001).Statistically significant value (P < 0.001); CI cognitive impairment.

Figure 2 .
Figure 2. Correlation between PA total metabolic equivalent and cardiac structure in hypertensive patients.The total metabolic equivalent of PA was negatively correlated with RVEDD and LAD in hypertensive patients (r = − 0.048, P = 0.030 (B); r = − 0.051, P = 0.020 (C)).There was no correlation between PA total metabolic equivalent and LVEDD in hypertensive patients (r = 0.026, P = 0.233 (A)).PA physical activity, RVEDD right ventricular end-diastolic diameter, LAD left atrial diameter.

Table 3 .
Correlation PA intensity and each part of MMSE scores in hypertensive patients.*Statistically significant value (P < 0.05).PA physical activity, MMSE Mini-mental State Examination.